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http://hdl.handle.net/11375/27355
Title: | Improving Adoptive Cell Therapy to Overcome Tumor Resistance |
Other Titles: | MS-275 Enhances Antitumor Immunity During Adoptive Cell Therapy to Overcome Tumor Resistance |
Authors: | Nguyen, Andrew |
Advisor: | Wan, Yonghong |
Department: | Medical Sciences |
Keywords: | Cancer Immunotherapy;Adoptive Cell Therapy;MS-275;HDAC Inhibitor;Tumor Resistance;Immunosuppression;T Cell Exhaustion;Epigenetic Reprogramming |
Publication Date: | 20-Dec-2021 |
Abstract: | Cancer immunotherapy has gained attention in recent years for its successes in potentiating immune responses that can elicit tumor control. In particular, adoptive cell therapy (ACT), which involves the autologous/allogeneic transplant of ex vivo-cultivated tumor-specific T lymphocytes, can mediate potent tumor recognition and killing; however, durable clinical responses are often difficult to obtain in solid tumors. Solid tumors and their unique microenvironments have the capacity to evade and suppress antitumor immune responses and represent significant hurdles for effective ACT. Recently, we have discovered that chemical inhibition of histone deacetylases via MS-275 (Entinostat) during ACT can subvert tumor resistance to foster potent, broad-spectrum antitumor immunity. Overall, the work described supports the efficacy of ACT in the treatment of immunosuppressive, solid tumors; however, consistency in durable clinical outcomes can only be achieved through the concurrent therapeutic targeting of tumor resistance mechanisms. This thesis uses pre-clinical models to describe how tumor resistance to ACT can manifest, and demonstrates that concurrent MS-275 delivery drives extensive immunomodulation to promote sustained tumor clearance. This includes: 1) The polarization of tumor-infiltrating myeloid cells into cytotoxic effectors with the ability to reject immune escape variants 2) The inflammatory remodeling of the tumor microenvironment to potentiate epitope spreading against secondary tumor antigens 3) The transcriptional reprogramming of adoptively transferred T cells to overcome tumor-burden-dependent exhaustion We expect that the results will help facilitate the development of next-generation ACT platforms that will feature strategies for multi-mechanistic perturbation of tumor resistance. |
URI: | http://hdl.handle.net/11375/27355 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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NGUYEN_ANDREW_T_FINALSUBMISSION202201_PHD.pdf | 46.04 MB | Adobe PDF | View/Open |
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